Advances in biomarkers for vasospasm - Towards a future blood-based diagnostic test

Abstract

Objective: Cerebral vasospasm and the resultant delayed cerebral infarction is a significant source of mortality following aneurysmal SAH. Vasospasm is currently detected using invasive or expensive imaging at regular intervals in patients following SAH, thus posing a risk of complications following the procedure and financial burden on these patients. Currently, there is no blood-based test to detect vasospasm.

Methods: PubMed, Web of Science, and Embase databases were systematically searched to retrieve studies related to cerebral vasospasm, aneurysm rupture, and biomarkers. The study search dated from 1997 to 2022. Data from eligible studies was extracted and then summarized.

Results: Out of the 632 citations screened, only 217 abstracts were selected for further review. Out of those, only 59 full text articles met eligibility and another 13 were excluded.

Conclusions: We summarize the current literature on the mechanism of cerebral vasospasm and delayed cerebral ischemia, specifically studies relating to inflammation, and provide a rationale and commentary on a hypothetical future bloodbased test to detect vasospasm. Efforts should be focused on clinical-translational approaches to create such a test to improve treatment timing and prediction of vasospasm to reduce the incidence of delayed cerebral infarction.

Keywords: Biomarker; Inflammation; Review; Subarachnoid hemorrhage; Vasospasm.

Fig. 1

PRISMA diagram.

Fig. 2

Mechanism of inflammation mediated vasospasm following SAH. Aneurysm rupture, hypertensive tumor related trauma, or other causes lead to SAH. Following SAH, the development of vasospasm is precipitated by ROS, inflammatory cytokines, and toxic blood breakdown byproducts. Inflammatory cytokines namely, IL-6, MCP-1, and TNF-α act on macrophages resulting in the activation of JAK2, STAT3, and NFkB, which perpetuate further inflammation. Macrophages also release additional ILs and MMPs further contributing to vasospasm. The thrombus formed in the aneurysm subsequently creates ROS further activating the sympathetic nervous system and NFkB and contributing to metabolic and mitochondrial dysfunction in microglia. Microglia then release miRNAs further exacerbating vasospasm. Heme from hemoglobin then activates the NLRP3 inflammasome complex which acts on the endothelium to release IL-6 and MCP-1. Vasospasm ultimately leads to cell death through macrophage activation and cytokine release, which presents an opportunity for pharmaceutical intervention. Some interventions already explored are NO and CO donors which prevent the formation of ROS.